Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5
Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5
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DOI：
10.1016/j.bbrc.2004.05.003
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发表时间：
2004-06-25
影响因子：
3.1
通讯作者：
Fruchart, JC
中科院分区：
文献类型：
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作者：
Fruchart-Najib, J;Baugé, E;Fruchart, JC
人类 APOA5 在小鼠中的过度表达导致血浆甘油三酯水平显着降低。在这项研究中，我们探讨了这种低甘油三酯效应的机制。最初，我们发现与对照组相比，hAPOA5 转基因小鼠的甘油三酯周转速度更快，这与肝素后血浆中 LPL 活性的增加密切相关。此外，我们表明体外重组 apoAV 与脂蛋白脂肪酶发生物理相互作用，并显着提高其活性。我们发现 hAPOA5 转基因小鼠中 apoB 和 apoCIII 均减少，表明 VLDL 数量减少。为了进一步研究 hAPOA5 在高脂血症背景下的机制，我们将 hAPOA5 和 hAPOC-3 转基因小鼠进行杂交。我们发现 VLDL 甘油三酯和胆固醇以及载脂蛋白 B 和 CIII 水平显着降低。这些数据表明，apoAV 通过激活脂肪分解和增加 VLDL 清除率来诱导 VLDL 大小的减少。在餐后状态下，野生型小鼠中正常的甘油三酯反应在 hAPOA5 转基因小鼠中显着降低。此外，我们证明，为了响应 hAPOA5 x hAPOC3 小鼠的这种脂肪负荷，apoAV（而非 apoCIII）从主要的 HDL 重新分配到 VLDL。 VLDL 中 apoAV 的这种转变似乎通过激活脂蛋白脂肪酶来限制甘油三酯的增加。 (C) 2004 Elsevier Inc. 保留所有权利。
Overexpression of human APOA5 in mice results in dramatically decreased plasma triglyceride levels. In this study we explored the mechanism underlying this hypotriglyceridemic effect. Initially we found that triglyceride turnover was faster in hAPOA5 transgenic mice compared to controls, and this strongly correlated with increased LPL activity in postheparin plasma. Furthermore, we show that in vitro recombinant apoAV interacts physically with lipoprotein lipase and significantly increased its activity. We show that both apoB and apoCIII are decreased in hAPOA5 transgenic mice indicating a decrease in VLDL number. To further investigate the mechanism of hAPOA5 in a hyperlipidemic background, we inter-crossed hAPOA5 and hAPOC-3 transgenic mice. We found a marked decrease in VLDL triglyceride and cholesterol, as well as apolipoprotein B and CIII levels. These data indicated that apoAV induces a decrease in VLDL size by activating lipolysis and an increase of VLDL clearance. In a postprandial state, the normal triglyceride response found in wild-type mice was significantly reduced in hAPOA5 transgenics. In addition, we demonstrated that in response to this fat load in hAPOA5 x hAPOC3 mice, apoAV, but not apoCIII, was redistributed from primarily HDL to VLDL. This shift of apoAV in VLDL appears to limit the increase of triglyceride by activating the lipoprotein lipase. (C) 2004 Elsevier Inc. All rights reserved.